Abstract

Changes in classical and nonclassical HLA class I as well as HLA class II antigens have been identified in malignant lesions. These changes, which are described in this review are believed to play a major role in the clinical course of the disease since both HLA class I and class II antigens are critical to the interaction between tumor cells and components of both innate and adaptive immune system. Abnormalities in HLA antigen expression in malignant cells, which range in frequency from 0-90%, are caused by distinct mechanisms. They include defects in beta(2)-microglobulin (beta(2)m) synthesis, loss of the gene(s) encoding HLA antigen heavy chain(s), mutations, which inhibit HLA antigen heavy chain transcription or translation, defects in the regulatory mechanisms, which control HLA antigen expression and/or abnormalities in one or more of the antigen processing, machinery (APM) components. More recently, epigenetic events associated with tumor development and progression have been found to underlie changes in HLA antigen, APM component, costimulatory molecule and tumor antigen (TA) expression in malignant cells. The types of epigenetic modifications that may occur in normal and malignant cells as well as their role in changes in HLA antigen expression by malignant cells have been reviewed. The epigenetic events associated with alterations in HLA antigen expression may be clinically relevant as, in some cases, they have been shown to impair the recognition of tumor cells by components of the adaptive immune system. The functional relevance and potential clinical significance of these epigenetic alterations have been addressed. Finally, unlike genetic alterations, epigenetic modifications can, in some cases, be reversed with pharmacologic agents that induce DNA hypomethylation or inhibit histone deacetylation. Therefore, strategies to overcome epigenetic modifications underlying changes in HLA antigen expression in malignant cells have been discussed.

Intracellular protein antigens, which are mostly endogenous, are marked for ubiquitination within the cytosol and subsequently degraded into peptides by proteasomal cleavage. Once generated, peptides are transported into the endoplasmic reticulum through the dimeric transporter associated with antigen processing, TAP1 and TAP2. Nascent, HLA class I heavy chains are synthesized in the ER and associate with the chaperone immunoglobulin heavy chain binding protein (BiP), a universal ER chaperone involved in the translation and insertion of proteins into the ER. Following insertion into the ER, the HLA class I heavy chain associates with antigen processing machinery components (APM), i.e., calnexin, ERp57, calreticulin and tapasin. The trimeric HLA class I‐b2m‐peptide complex is then transported to the plasma membrane where it plays a major role in the interactions between target cells and T cells. (A) Total HLA class I (HLA-A, -B and -C) loss is caused by loss of β2m expression and/or function; (B) Selective HLA class I allospecificity loss is caused by loss of the gene(s) which encode(s) the lost HLA class I allele(s) or by mutations which inhibit their transcription or translation; (C) Total loss of one HLA class I haplotype is caused by total or partial loss of one copy of chromosome 6 which encodes the genes for HLA class I heavy chains; (D) Total HLA class I downregulation is caused by loss or downregulation of APM components; (E) Selective HLA class I locus downregulation may be caused by locus-specific defects in HLA class I gene transcription.

In the nucleus the DNA double helix is wrapped around histone octamers to form nucleosomes, the basic structure of DNA inside the nucleus. (A) Modification of histones through methylation (-CH3) or acetlylation (-OCCH3) affects gene expression by targeting various protein complexes to DNA, resulting either in an open chromatin structure ready for expression or in a closed chromatin configuration that is impermeable to transcription factors and associated with gene silencing. (B) DNA methylation refers to the enzymatic addition of a methyl group to the 5 position of cytosine incorporated into DNA. In mammals, methylation is largely limited to cytosines that are part of the symmetrical dinucleotide CpG. A switch from unmethylated to methylated CpG island results in permanent loss of gene expression. (C) RNA interference (RNAi) is a post-transcriptional mechanism whereby gene expression is suppressed by RNA degradation, triggered by short stretches of complementary RNA. This process is a prominent mechanism of epigenetic regulation in plants and other organisms, where it plays roles varying from genome defense to chromosomal structure.

(A) Once the classical HLA class I-β2m-peptide complex is transported to the plasma membrane it plays a major role in the interactions between target cells and (a) activation of peptide-specific CTL through TCR; and (b) inhibition of T cell subpopulations through inhibitory receptors KIR. (B) In contrast to classical HLA class I, the non-classical HLA class I, HLA-G, inhibits CTL, CD4(+) T cells and NK cells through its interaction with the NK cells receptor CD94/NKG2. (C) HLA class II expression by tumor cells may be potentially beneficial to TA-specific immune responses through their interaction with CD4(+) T cells, resulting in the activation of (1) CD4(+) T cell-mediated killing, (2) macrophage through release of Th1 cytokines; (2) B cells and eosinophils through release of Th2 cytokines, and (4) CTL through release of Th1 cytokines.